Primary liver cancer is the third-leading cause of cancer-related mortality globally, accounting for over 700 000 deaths each year.1 In the last decade, the contribution of diet has been unravelled as a significant driver of hepatic oncogenesis.2 Specifically, diets high in fat have been associated with increased risk for the development of metabolic dysfunction-associated steatohepatitis (MASLD) and hepatocellular carcinoma (HCC) in many epidemiological studies,3 4 and these findings have been recapitulated in various in vitro and in vivo models. Although the link between diet and tumourigenesis has been convincingly established, the underlying mechanisms remain poorly understood.

In Gut, Bu et al hypothesised that exogenous metabolites from the diet might play a direct regulatory role in protein signalling and specifically in the activation of protein kinase B (AKT).5 The PI3K-AKT pathway is a well-characterised transducer of extracellular signals and promotes tumourigenesis by integrating environmental stimuli.6 Specifically in HCC, the role of PI3K-dependent AKT signalling has been an enduring focus of mechanistic and therapeutic investigations.7 In particular, it has been demonstrated that overexpression of an activated/myristoylated form AKT in the mouse liver via hydrodynamic gene delivery is sufficient to drive liver tumour development in a fatty acid-dependent manner.7 Post-translational modifications of AKT are a central regulatory component of the PI3K-AKT signalling pathway, with ubiquitination, methylation, and acetylation all uniquely modulating the function of AKT. More recently, two reports have shown that AKT can be palmitoylated in the context of lipogenesis and adipocyte differentiation8 and macrophage-induced colitis,9 but the mechanism of and role of AKT palmitoylation needs to be more thoroughly investigated.

Physiologically, the …